Filoviruses, Ebola viruses (EBOV) and Marburg viruses (MBGV) (NIAID category A), are extremely virulent causes of viral hemorrhagic fever. Effective small molecule anti-filovirus therapies are still lacking for these important biodefense pathogens. It has been previously demonstrated that EBOV or MBGV infection impairs the capacity of cells to produce interferon (IFN)-alpha/beta and impairs cellular responses to interferon (IFN)- alpha/beta and to IFN-gamma. These capacities likely contribute to the rapid in vivo dissemination of filoviruses and promote systemic filovirus infection and facilitate the replication of filoviruses in vivo. Defining the viral factors that block cellular responses to IFN should shed light on filoviral pathogenesis. The identification of compounds that block the function of filovirus-encoded IFN-antagonists could augment the efficacy of IFN produced during the course of viral infection or the efficacy of IFN administered as an antiviral treatment. We have identified the VP24 protein of EBOV and the VP40 protein of MBGV as inhibitors of IFN signaling. This proposal will capitalize upon the identification of the EBOV VP24 and MBGV VP40 as inhibitors of IFN signaling. We have already demonstrated that the EBOV VP24 inhibits the nuclear accumulation of activated STAT1, and preliminary data demonstrates that MBGV VP40 inhibits STAT1 and STAT2 tyrosine phosphorylation. Based upon these observations, the specific aims of this proposal are to (1) Define the mechanism by which the MBGV VP40 protein inhibits host cell IFN signaling; (2) Assess the importance of VP24 and VP40 for inhibition of IFN signaling in EBOV- or MBGV-infected cells; (3) Develop screens to identify inhibitors of EBOV VP24 and MBGV VP40 IFN-antagonist function; and (4) Identify small molecules that inhibit EBOV VP24 and MBGV VP40 function.